The present invention relates to a pharmaceutical drug; more specifically, the invention relates to a therapeutic agent for reducing pain in an endothelin-induced disease, such as prostate cancer; a therapeutic agent for ameliorating osteogenic disorders and/or a therapeutic agent for reducing pain involved in osteogenesis; a therapeutic agent for reducing pain involved in the bone metastasis of prostate cancer and/or a therapeutic agent for ameliorating osteogenic disorders due to the bone metastasis of prostate cancer; a therapeutic agent for suppressing the growth of the cancer cell of prostate cancer; or a therapeutic agent for suppressing the progress of prostate cancer.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfoneamide or a salt thereof is described in the International Patent Publication No. 97/22595. The actions thereof to suppress ET-1 binding to endothelin ETA receptor and to suppress ET-1 induced vascular constriction and blood pressure elevation are disclosed therein, indicating that the compound or a salt thereof can be used for treating various diseases primarily including cardiovascular diseases, for which endothelin is responsible.
For the purpose of creating a new therapeutic agent, the present inventors have made more detailed investigations about a possibility of the application of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a salt thereof to the treatment of diseases,
Consequently, the inventors have found that N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a salt thereof is effective for the reduction of pains of endothelin-induced diseases, such as cancer (particularly, prostate cancer, breast cancer, ovarian cancer), arthritis, prostatitis, glioma, peripheral artery occlusion, dysmenorrhea, migraine headache, angina, acute cardiac infarction, cerebral infarction, subarachinoid hemorrhage, diabetic nervous disorders, rheumatoid arthritis, glaucoma, gastric ulcer and labor during delivery. Thus, the invention has been achieved.
It is reported that ET-1 induces pain in humans and experimental animals. For example, ET-1 administered to human brachial artery induces ischemic muscular pain (J.Hypertension,8,811-817,1990). Additionally, it is reported that ET-1 significantly enhances the first and second phases of pain due to formalin in the mouse formalin pain model commonly used as a pain model. (Can.J.Physiol.Pharmacol.,75,596-600,1997). In the model, the first phase means pain due to direct stimulation of sensory nerve, while the second phase means pain due to inflammatory secondary reaction (Pain,38,247-352,1989).
As shown in the following Test Example 1, The effective component of the invention exerted an action to suppress the enhancement of pain induced by ET-1 in the mouse formalin pain model.
Further, the inventors have found that N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a salt thereof is effective for the amelioration of osteogenic disorders and/or the reduction of pain involved in osteogenesis. Thus, the invention has been achieved.
Because bisphosphonates with an action to suppress osteoclast and thereby ameliorate bone metabolism have an effect to ameliorate bone pain involved in the bone metastasis of breast cancer, the amelioration of long-term bone disorders is believed to lead to the amelioration of bone pain. Unlike bread cancer patients with bone metastasis, osteogenic disorders due to bone metastasis are observed in patients with prostate cancer (Semin.,Oncol.,21,630-656,1996), and drugs with an action on osteoblast to thereby ameliorate bone metabolism probably have an effect to ameliorate bone pain involved in the bone metastasis of prostate cancer.
It is reported that ET-1 exerts actions to increase intracellular Ca2+ concentration and DNA synthesis and to reduce ALP activity through ETA receptors in MC3T3-E1, mouse osteoblast-like cells, and osteoblast primarily cultured from a rat calvaria (Am.J.Physiol.,257,E797-E803,1989/Biochem.Biophys.Res.Commun.,170(3),998-1005,1990/Bone,21(2),143-146,1997).
As shown in the following Test Example 2, The effective component of the invention exerted an action to suppress the ET-1-induced cell response reactions of the MC3T3-E1, mouse osteoblast-like cells.
Further, the inventors have found that N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a salt thereof is effective for the amelioration of osteogenic disorders due to the bone metastasis of prostate cancer and/or the reduction of pain involved in the bone metastasis of prostate cancer. Thus, the invention has been achieved.
It is reported that a human prostate cancer cell line has a potency to generate ET-1 (Nat.Med.,1(9),944-949,1995) and the growth potency is exerted through ETA receptors (Cancer Res. ,56,663-668,1996) and that the plasma ET-1 concentration in prostate cancer patients with bone metastasis is elevated, compared with the ET-1 concentration in prostate cancer patients without bone metastasis (Nat.Med.,1(9),944-949,1995). Taking account of these reports together with the results of Test Examples 1 and 2, the effective component of the invention is believed to be particularly effective for the amelioration of osteogenic disorders due to the bone metastasis in prostate cancer patients and/or the reduction of pain involved in the bone metastasis of prostate cancer patients. Additionally, as shown in the following Test Example 5, the effective component of the invention reduced pain score and use of analgesics in prostate cancer patients, and decreased bone metabolism markers in prostate cancer patients.
Further, the inventors have found that N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a salt thereof is effective for the suppression of the growth of the cancer cell of prostate cancer. Thus, the invention has been achieved.
As shown in the following Test Example 3 and 4, The effective component of the invention suppressed cell growth of hormone-refractory human prostate cancer cell induced by ET-1.
Further, the inventors have found that N-[6-methoxy-5-(2- methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a salt thereof is effective for the suppression of the progress of prostate cancer. Thus, the invention has been achieved.
As shown in the following Test Example 5, The effective component of the invention stabilized or decreased Prostate cancer marker PSA in prostate cancer patients.
In other words, the invention relates to a pharmaceutical composition for reducing pain in endothelin-induced diseases, such as cancer (particularly, prostate cancer, breast cancer, ovarian cancer), arthritis, prostatitis, glioma, peripheral artery occlusion, dysmenorrhea, migraine headache, angina, acute cardiac infarction, cerebral infarction, subarachinoid hemorrhage, diabetic nervous disorders, rheumatoid arthritis, glaucoma, gastric ulcer and labor during delivery; a pharmaceutical composition for ameliorating osteogenic disorders; and/or a pharmaceutical composition for reducing pain involved in osteogenesis, particularly a pharmaceutical composition for ameliorating osteogenic disorders due to the bone metastasis of prostate cancer; and/or a pharmaceutical composition for reducing pain involved in the bone metastasis of prostate cancer, the aforementioned compositions containing N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a pharmaceutically acceptable salt thereof as the effective components.
Additionally, the invention relates to the use of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reducing pain of endothelin-induced diseases such as prostate cancer; a medicament for ameliorating osteogenic disorders; and/or a medicament for reducing pain involved in osteogenesis, particularly a medicament for ameliorating osteogenic disorders due to the bone metastasis of prostate cancer: and/or a medicament for reducing pain involved in the bone metastasis of prostate cancer.
Additionally, the invention relates to a method for reducing pain of endothelin-induced diseases such as prostate cancer and/or pain involved in osteogenesis, particularly pain involved in the bone metastasis of prostate cancer, comprising administering a therapeutically effective dose of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a pharmaceutically acceptable salt thereof to such patients. Still additionally, the invention relates to a method for ameliorating osteogenic disorders, particularly osteogenic disorders due to the bone metastasis of prostate cancer, comprising administering a therapeutically effective dose of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a pharmaceutically acceptable salt thereof to such patients.
The invention relates to a pharmaceutical composition for suppressing the growth of the cancer cell of prostate cancer and/or a pharmaceutical composition for suppressing the progress of prostate cancer, the compositions containing N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a pharmaceutically acceptable salt thereof as the effective components.
Additionally, the invention relates to the use of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for suppressing the growth of the cancer cell of prostate cancer and/or a medicament for suppressing the progress of prostate cancer.
Further, the invention relates to a method for suppressing the growth of the cancer cell of prostate cancer, comprising administering a therapeutically effective dose of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a pharmaceutically acceptable salt thereof to such patients. Furthermore, the invention relates to a method for suppressing the progress of prostate cancer, comprising administering a therapeutically effective dose of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a pharmaceutically acceptable salt thereof to such patients.
Because The effective component of the invention is particularly excellent in terms of oral absorptivity, the compound can be modified into an excellent oral therapeutic agent. As shown in the following Test Example 6. the plasma concentration thereof when orally administered to humans at a dose xc2xd-fold that of ABT-627[1-(N,N-dibutylcarbamoylmethyl)-2(R)-(4-methoxyphenyl)-4(S)-(3,4-methylenedioxyphenyl)pyrrolidine-3(R)-carboxylic acid] as a known ETA receptor antagonist is prominently great with AUC of about 18-fold.
The invention is described in more detail hereinbelow.
The effective component of the inventive pharmaceutical composition is N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a pharmaceutically acceptable salt thereof. Such salt includes the salt described in the International Patent Publication No. 97/22595 and its specific examples are acid addition salt such as a salt with inorganic acid (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid) or organic acid (for example, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid and glutamic acid) and a salt with base such as inorganic base (for example, sodium, potassium, magnesium, calcium and aluminum) and organic base (for example, methylamine, ethylamine, ethanolamine, lysine and ornithine) as well as ammonium salt. Particularly preferable is the potassium salt thereof.
The effective component of the invention includes all of mixtures of various isomers thereof and isolated various isomers thereof, hydrated products thereof and solvated products thereof. Additionally, the inventive effective component is sometimes of crystal polymorphism, so the inventive effective component includes all the crystals thereof.
These compounds are readily available by the production method described in the International Patent Publication No. 97/22595 or according to the production method.
The drug of the invention can be prepared as oral solid dosage form, oral liquid dosage form or injection, by using organic or inorganic carriers, excipients and other additives suitable for oral or parenteral administration, according to routine methods. Owing to the great oral absorptivity of the effective component of the invention, the drug of the invention is suitable for oral dosage form. The most preferable is an oral solid dosage form, which can be readily incorporated by patients by themselves and are convenient for storage and transfer.
The oral solid dosage form includes tablet, powder, fine particle, granule, capsule, pill and sustained-release type. In such solid dosage forms, one or more active substances are mixed with at least one inactive diluent, for example lactose, mannitol, glucose, micro-fine cellulose, starch, cornstarch, polyvinylpyrrolidone and metasilicate aluminate magnesium. According to routine methods, the composition may satisfactorily contain additives other than inactive diluents, including for example binders such as hydroxypropyl cellulose and hydroxypropylmethyl cellulose (HPMC); lubricants such as magnesium stearate, polyethylene glycol, starch and talc; disintegrators such as fibrinogen calcium glycolate and cermellose calcium; stabilizers such as lactose; dissolution auxiliary agents such as glutamic acid or aspartic acid; plasticizers such as polyethylene glycol; and colorants such as titanium oxide, talc and yellow ferric oxide. If necessary, the resulting tablet or pill may satisfactorily be coated with sugar coating or films comprising substances solubilizable in stomach or intestine, such as sucrose, gelatin, agar, pectin, hydroxypropyl cellulose and hydroxypropylmethyl cellulose phthalate.
The oral liquid dosage form includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs and contains inactive diluents for general use, for example distilled water and ethanol. Other than inactive diluents, the composition may satisfactorily contain auxiliary agents such as moisturizers and suspending agents, sweeteners, flavor, fragrance, and preservatives.
Injections for intravenous, intra-muscular and subcutaneous injection include sterile aqueous or non-aqueous solutions, suspensions and emulsions. The diluents for the aqueous solutions and suspensions include for example distilled water for injections and physiological saline. The diluents for the non-aqueous solutions and suspensions include for example propylene glycol, polyethylene glycol and vegetable oils such as olive oil, alcohols such as ethanol and polysorbate 80. Such composition may additionally contain auxiliary agents such as preservatives, moisturizers, dispersants, stabilizers (for example, lactose), and dissolution auxiliary agents (for example, glutamic acid, aspartic acid). These are sterilized by filtration through bacteria trapping filters or blending with sterilizing agents or under irradiation. These may satisfactorily be used to produce sterile solid compositions, which are dissolved in sterile water or sterile solvents for injections prior to use, and are then used.
The dose of the compound as the effective component of the invention is appropriately determined, depending on each case, taking account of dosage route, diseased conditions, and the age and sex of a dosing subject, but for general administration, the dose of the effective component is about 0.1 to 500 mg/day, preferably 1 to 250 mg/day, per one adult, which is then administered in two-dividend portions.
Herein, the inventive drug can be used in combination with other pain reducing agents, simultaneously or separately in terms of dosing time. For cancerous pain due to prostate cancer and breast cancer, for example, the pain reducing agents include strong opioid analgesics such as morphine for use in the WHO therapeutic mode of cancerous pain, weak opioid analgesics such as pentazocine and buprenorphine, and non-steroidal anti-inflammatory analgesics such as indometacin and ibuprofen.
The inventive drug can be used in combination with other drugs for the therapy of endothelin-induced diseases, simultaneously or separately in terms of dosing time. Therapeutic agents of prostate cancer, which can be used in combination with the inventive drug, include anti-malignant tumor agents such as ifosfamide, tegafurxe2x80xa2uracil, estrogen such as ethynylestradiol, adrenal cortex hormones such as hydrocortisone, prednisolone and bemethazone, progesterone such as chloropromazine acetate, LH-RH derivatives such as leuprorelin acetate, LH-RH agonists such as goserelin acetate. anti-malignant tumor platinum complex compounds such as cisplatin, anti-androgen agents such as flutamide, therapeutic agents of prostate cancer, such as fosfestrol and sodium phosphate estramustine, and anti-tumor antibiotics such as peplomycin sulfate.